Apparatus and method for monitoring the validity of a molecular model

ABSTRACT

A computer implemented molecular modeler displays information concerning structural validity to the user. The display of information may be updated substantially continuously while the user modifies the molecular model. The display of information may comprise a color coded indicator and/or text associated with the atoms of the molecular model.

CROSS REFERENCE OF RELATED APPLICATONS

[0001] This application is a continuation of U.S. patent applicationSer. No. 09/312,234 filed May 14, 1999.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The invention relates to computer implemented molecular modelingtools and the display of molecular structures to a user.

[0004] 2. Description of the Related Art

[0005] Chemists often find it desirable to visualize the structure ofmolecules in two or three dimensions. In rational drug designapplications, for example, functional interactions between proteins andligands can be illustrated by an analysis of the three dimensionalstructure of the two molecules. Protein-ligand binding sites, forexample, may be discovered using such three dimensional models. Althoughsuch models were originally done with physical ball-and-stick or spacefilling kits, computer programs and high resolution graphic displayshave become regularly used for the visualization of multidimensionalmolecular models. With these programs, a chemist can input a selectedset of atoms and their bonds, thereby defining a molecular structure fordisplay and analysis.

[0006] Originally, these computer programs were used mainly by highlytrained computational chemists that specialized in the use of computermodels to understand and predict chemical behavior. Over the pastseveral years, however, bench chemists, biologists, and otherresearchers that work predominantly in the wet laboratory environmenthave begun to utilize computer modeling techniques to a much greaterextent. This development has spurred the need to provide molecularmodeling tools which are more user friendly than those previouslyavailable in the past.

[0007] In some currently available computer modeling programs, thephysical validity of a molecular structure is evaluated automatically.It is well known to those in the art that one important aspect of thephysical validity of a given molecular model is the satisfaction of thevalences for each atom of the molecule. For example, the orbitalconfiguration of the four valence shell electrons in carbon define a setof covalent bond structures for this element. Each of theseconfigurations requires a total of four bonds between a given carbon andits covalently bonded partners to satisfy the valence of a given carbonatom. Similar considerations are present for other elements. Oxygen, forexample requires two bonds for valence satisfaction.

[0008] With validity checking features as part of a molecular modelingprogram, the user may receive information from the program indicatingwhether or not a given atom has under or over filled valences. Thisfeature may take a number of forms. In some programs, the user mayselect an atom, and a text window is displayed which includes anindication of the atom's valence status. If desired, the user may thenclose the text window and return to the molecular design algorithm tocorrect any problems set forth therein.

[0009] In a program commercially available under the name ISIS Draw™,from MDL Information Systems Inc., the user is informed when an overvalence condition is about to be created during the process of designingthe molecular structure. The user is then given the option to eitherrefrain from placing the bond which will create the over valencecondition, or to disable the validity checking from that atom. In thelatter case, no further warnings are delivered to the user if additionalbonds are made to the already over hybridized atom. ISIS Draw™ can alsocheck the structure with a separate subroutine after the drawing iscomplete. This subroutine informs the user of problems, but does notidentify the invalid atoms.

[0010] In a web-based program called Test Grins, available from DaylightChemical Information Systems, Inc., the user first types a desiredstructure, and then runs a separate subroutine which checks thestructure for over and under valenced atoms. The user may then return tothe molecular design algorithm, and correct the problem atoms and/orbonds if desired.

[0011] In another program called CS ChemDraw, available fromCambridgeSoft, the user can check the structure with a separatesubroutine after the drawing is complete. This subroutine indicatesproblems with the molecular structure by highlighting one atom at atime.

[0012] In each of these cases, the information provided to the user isin a format which is relatively difficult to access and use, and in somecases does not indicate the portion of the molecular structure that isincorrect. Instant availability of information relating to the validitystatus of the atoms of a molecule being designed is not provided. Thereis therefore a need in the art to present this information to chemistsperforming computer implemented molecular modeling in a more userfriendly format.

SUMMARY OF THE INVENTION

[0013] In one embodiment, the invention comprises a method of modelingmolecular structure comprising the display of information representativeof the physical invalidity of a modeled molecular structure andsimultaneously accepting commands from a user to modify the modeledmolecular structure.

[0014] The invention also comprises apparatus molecular modeling. In oneembodiment, such apparatus comprises a display device for outputting amultidimensional representation of a user-defined molecular structureand an input device for receiving user commands to modify the userdefined molecular structure. The apparatus further comprises a structuremonitor comprising a plurality of validity attributes associated with arespective plurality of atoms of the user-defined molecular structure.The structure monitor is coupled to the display device so as to displayinformation representative of a current status of the plurality ofvalidity attributes. The structure monitor is coupled to the inputdevice such that the current status is modified in response to usercommands to modify the molecular structure. Thus, the display ofinformation is updated as the molecular structure is modified by a user.

[0015] Another aspect of the invention comprises a computer readablemedia having instructions stored thereon which configure a generalpurpose computer to perform a method of molecular modeling comprisingthe simultaneous performance of (1) displaying informationrepresentative of physical invalidity of a molecular model and (2)accepting commands from a user to modify the molecular model.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016]FIG. 1 is a perspective view of the computer environment themolecular modeler of the invention.

[0017]FIG. 2 is a screen display of a molecular model comprising atomshaving properly filled valence shells.

[0018]FIG. 3 is a screen display of a molecular model wherein valencesfor some atoms are improperly filled.

[0019]FIG. 4 is a block diagram of a portion of the components of themolecular modeler of the invention.

[0020]FIG. 5 is a flow chart of a process of updating a display of amolecular model in one embodiment of the invention.

[0021]FIG. 6 is an alternative screen display of the structurallyinvalid molecular model of FIG. 3.

[0022]FIG. 7 is another alternative screen display of the structurallyinvalid molecular model of FIG. 3.

[0023]FIG. 8 is another alternative screen display of the structurallyinvalid molecular model of FIG. 3.

[0024]FIG. 9 is a screen display of a dialog box utilized by a user ofone embodiment of the molecular modeler to modify the display ofvalidity information.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0025] Embodiments of the invention will now be described with referenceto the accompanying Figures, wherein like numerals refer to likeelements throughout. The terminology used in the description presentedherein is not intended to be interpreted in any limited or restrictivemanner, simply because it is being utilized in conjunction with adetailed description of certain specific embodiments of the invention.Furthermore, embodiments of the invention may include several novelfeatures, no single one of which is solely responsible for its desirablequalities or which is essential to practicing the inventions hereindescribed.

[0026] Referring now to FIG. 1, the molecular modelers of the inventioncomprise software code which configures a general purpose computer todisplay multidimensional models of user defined molecular structures.The code is typically provided to a user on a computer readable mediumsuch as a CD-ROM or floppy disk. Once installed on a computer, the codeis generally stored on a hard disk drive in the user's computer system.The nature of the computer may vary widely, and may include mainframes,mini-computer workstations, or personal microcomputers. As illustratedin FIG. 1, the host computer system comprises data processing hardware12 including a computer readable memory such as semiconductor RAM and ahard disk drive for storing the code, as well as an associated display14. The host system also typically includes input devices such as akeyboard 16 and mouse 18 for accepting user commands. It will beunderstood that the host hardware is conventional in nature and will notbe described in further detail.

[0027] Also illustrated in FIG. 1 is a user interface 20 which is outputon the display 14. This interface includes a region containing a displayof a user-defined molecule 22, and may also include toolbars 24 defininguser commands allowing modification and manipulation of the displayedmolecule 22. User modification of a molecule may include the ability toadd and delete atoms from the molecule, to change an atom from oneelement to another, or to alter bonds from, for example, a single bondto a double bond. The user may also be able to rotate or otherwisemanipulate the display of the model. A wide variety of alternatives forthe mouse and keyboard implemented alteration and manipulation ofmolecular model displays are known in the art, and may advantageously beused in conjunction with the invention described herein. One specificexample for the task of drawing two dimensional molecular structures isdescribed in U.S. Pat. No. 5,461,580 to Facci, et al., the disclosure ofwhich is hereby incorporated by reference in its entirety.

[0028]FIG. 2 is an example screen display of a physically validmolecular model which may be displayed by a molecular modeling programin accordance with the invention. The display is in three-dimensional“ball and stick” format, and includes three joined ring structures. Twoof the three ring structures 30, 32 are formed entirely from carbonatoms, and one of the rings 34 includes an oxygen atom 36. In thedisplay embodiment of FIG. 2, oxygen atoms are indicated by differentcross hatching styles. Hydrogen atoms 38 are indicated by a thirddifferent cross hatching style than both oxygen atoms and carbon atoms.In many advantageous embodiments of computer based molecular modelingprograms, the different elements are color coded. For example, carbonmay be displayed as gray, oxygen as red, and hydrogen as yellow. Otherelements such as nitrogen, sulfur, etc. may be indicated by additionalcolors. The different cross hatching of FIG. 2 indicates this differentperceived coloring to a user of the program. For clarity, this crosshatching for color indication is omitted from FIGS. 6, 7 and 8.

[0029] The molecular structure set forth in FIG. 2 has satisfiedvalences for all atoms in the structure. Of particular interest in thediscussion below are the two sp² hybridized carbon atoms 42, 44, and thesp³ hybridized carbon atom 46. It may also be noted that the oxygen atom48 has a properly-satisfied valence via the double bond 50 between itand the covalently bound carbon atom 44.

[0030] In FIG. 3, the molecular model of FIG. 2 has been modified toinclude improperly valenced atoms. In FIG. 3, the carbon atom 42 hasbeen triple bonded to an adjacent carbon in the ring 30, rather thandouble bonded as shown in FIG. 2. This carbon atom 42 is now hasover-filled valences, having five covalent bonds to neighboring atoms.In addition, the bond 50 between carbon atom 44 and oxygen atom 48 hasbeen changed from a double bond to a single bond. This results in boththe carbon atom 44 and the oxygen atom 48 having un-filled valences.Another modification is the removal of a hydrogen from carbon atom 46 ofFIG. 2. Thus, this carbon atom 46 now has un-filled valences.

[0031] As can be seen in FIG. 3, the status of each of these atoms asimproperly valenced is displayed in association with the relevant atom.In the embodiment illustrated in FIG. 3, one displayed feature whichindicates the improperly valenced atoms is a surrounding “cage” 52. Thiscage 52 may be a different color depending on whether or not the atomhas an under-filled or over-filled valence shell. For example, the cagearound the over valenced atom 42 may be red, and the cage around theunder-valenced atoms 44, 46, 48 may be yellow. A textual explanation ofthe valence problem may also be provided. In the embodiment of FIG. 3,for example, the under valenced atoms are provided with a legend stating“Under valence”.

[0032] Advantageously, these displayed features which indicate thephysical invalidity of a portion of a molecular model are updated anddisplayed substantially continuously as modifications to the molecularmodel are made by the user. Referring now to FIG. 4, this updating isaccomplished by a structure monitor 56 provided as part of the modelingprogram. The structure monitor 56 comprises one or more validityattributes respectively associated with one or more of the atoms of themodeled molecule. In some advantageous embodiments, all atoms areassigned an associated validity attribute, although in some cases only aselected subset of atoms may have associated validity attributes. Thesevalidity attributes associated with the atoms track the physicalvalidity status of the atoms of the molecular model.

[0033] The structure monitor 56 is coupled to both the user input 58,and the display 60. As the user modifies the molecular model with userinput 58, both the validity attributes of the structure monitor 56 andthe display 60 of the molecule itself are modified. Furthermore, theupdated content of the validity attributes is sent to the display 60such that these features, associated with the atoms, which indicate anyphysical invalidities are substantially continuously updated along withthe display of the molecule.

[0034]FIG. 5 is a flowchart setting forth a method of updating amolecular display and an associated physical validity display in oneembodiment of the invention. The method begins at a start state 64 andmoves to a decision state 66 where the user decides whether to modifythe structure of the molecular model. If modification is desired, atblock 68 the user uses input devices such as the computer keyboard ormouse to define and enter the desired modification. The modification maycomprise the addition or deletion of an atom or a group of atoms such asa ring or alkyl chain, the alteration of a bond between existing atoms,changing an atom from one element to another, etc. The modification mayalso comprise the creation of the first atom or multi-atom element of anew molecular structure being modeled. After the modification is input,validity attributes are calculated at block 70 for all or a selected setof the atoms of the modeled molecule. When a new atom is added to themodel, a validity attribute associated with this new atom may becalculated. If the number of bonds is insufficient to fill the valenceshell, the calculated validity attribute will indicate “under valence”.Furthermore, the validity attribute associated with the atom to whichthe added atom is bonded may be re-calculated as “over valence”, whenprior to the modification it was calculated as properly valenced. Thus,each user defined change to the molecular model results in arecalculation of validity attributes for some or all of the atoms of themodel.

[0035] At block 74, the molecular model is displayed with themodifications made by the user. At block 78, the updated status of thevalidity attributes for the atoms of the molecule are also displayed.Therefore, the user is provided with substantially constant feedbackregarding the physical validity of the molecular model being analyzed.Preferably, the updating of the molecular display and the updating ofthe displayed invalidity information occurs substantially simultaneouslyfor the user of the modeling program. That is, the displayed informationconcerning invalidities is modified continually while the user isviewing and modifying the molecular model. Validity checking therebybecomes a more interactive and useful tool for chemists using computerimplemented molecular modeling. Users may, for example, view invalidityinformation associated with an atom of a molecular model, andsimultaneously enter a modification to a bond so that the displayedinvalidity information is altered. This alteration may comprise theelimination of the display indicating a physical invalidity. Thus, ifthe structure modification made by the user cures the valence problem,the display of may disappear as the modification is made. The user maytherefore watch valence invalidities disappear in real time as the usermodifies the molecule.

[0036] After the molecule and the displayed invalidity information isupdated, the method of FIG. 5 loops back up to the decision block 66,where the user again determines whether to modify the molecularstructure being modeled. If not, the method moves to end state 78. Ifadditional modifications are desired, the process of updating thevalidity attributes and the display of the molecule and invalidityinformation is repeated as described above.

[0037] It will be appreciated that the invalidity information and themolecule can be displayed in many different formats. In FIG. 6, forexample, the textual legend which appears in FIG. 3 is omitted. In FIG.7, the molecule is presented in a “line” drawing rather than a ball andstick format. In this case, the colored cages surround endpoints of thelines where the relevant atoms reside. In FIG. 8, the colored cagessurround the relevant atoms of a space filling representation of themodeled molecule of FIG. 3.

[0038] In one advantageous embodiment of the invention, the nature ofthe display of invalidity information is user configurable. In thisembodiment, the user may define the features which are displayed inassociation with the atoms of the molecule to indicate physicalinvalidity. FIG. 9 illustrates one implementation of this feature. ThisFigure illustrates a dialog box 80 that is user accessible. It may beuser accessible through one of the toolbars 24 of FIG. 1 for example.This dialog box 80 sets forth at least some of the properties of thestructure monitor 56 of FIG. 4. In the embodiment of FIG. 9, the userhas a yes/no toggle 82 for selecting whether or not under valenced atomsare indicated as invalid or are instead, for example, assumed to havetheir valence completed by adding hydrogen atoms. The user also hasanother yes/no toggle 84 in this dialog box 80 for determining whether atextual explanation is provided for the valence problem. Thus, in someadvantageous embodiments of the invention, the user may control whatvalidity problems are displayed and/or how those problems are indicated.The dialog box may also indicate the total number of improperly valencedatoms. In the embodiment of FIG. 9, the number of under-valenced andover-valenced atoms are separately set forth.

[0039] It will be appreciated that a wide variety of implementations ofthe above described invention are possible while retaining itsadvantageous user interactive features. In this discussion, the propervalence status of the atoms of the molecule is the focus of themolecular validity analysis. However, those of skill in the art willrecognize that validity attributes could also be associated withindividual bonds of the structure, and may, for example, indicate to auser if a bond is too short or too long. Similar substantiallycontinuously updated invalidity information could be provided for bondangles, non-bonded interatomic distances, as well as a variety of otherparameters. In addition, the user may be provided with a wide variety ofoptions for which types of information is displayed and the format it isdisplayed in. In some advantageous embodiments, the user may be allowedto choose different display options for different atoms and bonds.

[0040] The foregoing description details certain embodiments of theinvention. It will be appreciated, however, that no matter how detailedthe foregoing appears in text, the invention can be practiced in manyways. As is also stated above, it should be noted that the use ofparticular terminology when describing certain features or aspects ofthe invention should not be taken to imply that the terminology is beingre-defined herein to be restricted to including any specificcharacteristics of the features or aspects of the invention with whichthat terminology is associated. The scope of the invention shouldtherefore be construed in accordance with the appended claims and anyequivalents thereof.

What is claimed is:
 1. A method of modeling a molecular structurecomprising: assigning a validity attribute to at least one atom of saidmolecular structure; and displaying a user-defined feature associatedwith said atom, said feature representing at least a portion of thecontent of said validity attribute.
 2. The method of claim 1, whereinsaid displaying a feature comprises displaying text.
 3. The method ofclaim 1, wherein said displaying a feature comprises displaying a userdefined color associated with said atom.
 4. The method of claim 3,wherein said displaying a feature comprises displaying text.
 5. Themethod of claim 1, additionally comprising assigning a validityattribute to at least one bond of said molecular structure.
 6. Themethod of claim 1, wherein said validity attribute comprises informationconcerning under-filled and over-filled valence shells for said atom. 7.A method of modeling molecular structure, comprising: displaying a usermodifiable molecular structure; and while the molecular model is beingdisplayed and modified by the user, providing the user with automaticand substantially continuous displayed feedback regarding the physicalvalidity of the entire molecular structure as the user performs a seriesof modifications, each of which modifies only an individual atom or bondof the molecular structure.